HIV protease inhibitors have been part of highly active therapy regimens throughout the past 16 years of antiretroviral therapy. The majority of currently available protease inhibitors are coadministered with low-dose ritonavir (RTV) as a pharmacoenhancer, significantly increasing their plasma concentrations. This therapeutic principle called 'boosting' helped to overcome the obstacles of this class of drugs concerning unfavorable pharmacokinetics, resulting in either a high frequency of dosing or subtherapeutic plasma concentrations. The coadministration of RTV together with HIV protease inhibitors created a potent, clinically effective antiretroviral therapy, which is more convenient for the patient, and has revealed a high genetic barrier to viral resistance. RTV is the only pharmacoenhancing agent available to date; however, cobicistat, a selective CYP3A4 inhibitor, is about to enter the market. This article reviews current literature, compares the safety of both pharmacoenhancers and appraises their use in current and future HIV therapy.